Abstract Post acute phase of ionizing radiation (IR), survivors face two unavoidable challenges: IR pneumonitis in months and lung fibrosis in years. The unique characteristic of IR-induced lung damage is its endless sterile inflammation cascade. IR pneumonitis progress into lung fibrosis, an irreversible lost of lung function that can greatly reduce the quality of life and eventually cost life. Currently, there is no drug for blocking the progression of this devastating disease. The underlying mechanism for this long-lasting pathological process is unclear, however, some facts are clear: 1) there are no infection pathogens;2) it is a long-lasting inflammation process (months-years);3) it becomes worsen with times, until fibrosis has formed and organ function is destroyed;4) the IR lung tissue is the target of immune reaction;and 5) immune suppressors (steroids) are effective but transient and can not be used in a long run. These facts strongly suggest that the immune reaction play a major role in the progression of IR pneumonitis and lung fibrosis. Based on this concept, we have been searching for anti-immune agents to mitigate the IR lung injury for 4 years and found that triptolide (TPL, MW 360, purified from the traditional medicinal herb Tripterygium wilfordii Hook F) reduces both IR pneumonitis and lung fibrosis as evidenced by: 1) At the acute phase, when TPL was given orally for 2 days at a dose of 0.25 mg/kg/daily after 15 Gy thorax IR, it reduced the number of lymphocytes in the BALF (bronchial alveolar lavage fluid), the lung infiltrated inflammatory cells and exudates and MPO (myeloperoxidase) activity, the plasma pro-inflammation cytokines, such as IL1[unreadable], TNF[unreadable], lymphotaxin, IL6, ICAM-1, P-selectin, and plasma SP-D (surfactant protein D, released due to IR lung damage);2) At the sub-acute phase, the use of TPL (0.25 mg/kg orally, qod for 17 days) reduced the severity of pneumonitis, as evidenced by fewer infiltration cells in both BALF and lung, and a reduced plasma SP-D, lymphotaxin, IL6, ICAM-1, IL15, P-selectin, etc;3) At late phase, the use of TPL (0.25 mg/kg qod or q3d for 3-6 months) reduced the severity of lung fibrosis at 7-12 months as evidenced by improved lung function (lower respiratory rate and higher lung compliance), reduced lung fibrosis (low density in cone beam CT scan, less fibrosis in H&E and Trichrome staining), decreased hydroxyproline content and reduced IL1a, IL6 and ICAM-1 in lung tissue;and 4) The therapeutic dose of TPL for 3-6 months was well tolerated. Based on the mitigation data and its stable and easy to use, we hypothesize that TPL is an effective mitigator for IR pneumonitis and lung fibrosis. To maximize the TPL beneficial effect, we will focus on the following aims: 1) To define the optimal dose, starting time, and schedule for utilizing TPL to mitigate IR pneumonitis;2) To determine the optimal schedule for IR lung fibrosis. This project is likely to develop TPL as an effective mitigator of IR pneumonitis and lung fibrosis for mass nuclear casualty. It will also be of benefit to lung cancer patients with radiotherapy.